The ability of mu opioid receptor agonists to reduce intraocular pressure (lOP) in both human and animals has been firmly established. The mu-3 opioid receptors are opiate alkaloid selective receptors that are insensitive to opioid peptides. In response to stimulation by an opioid alkaloid like morphine, mu-3 receptor activation leads to the release of nitric oxide (NO). In the eye, NO is a physiological regulator as well as a pathological mediator not only in the vascular system but also in other ocular tissues including the retina and choroid. In addition the human outflow pathway and ciliary muscle have been shown to be enriched with sites of NO synthesis. The overall objective of the proposed project is to establish the presence and functional activity of mu-3 opioid receptors in outflow tracts of the rabbit eye. If present, functionally this type of opioid receptor may be involved in the regulation of outflow facility thereby regulating lOP. The proposed study will test the hypothesis that mu-3 opioid receptors are present in the outflow tracts of the eye where they regulate lOP through NO-mediated signaling events. Studies proposed to test the hypothesis include: (1) determining the effect of mu-3 opioid receptor activation on ocular hydrodynamics; (2) establishing the functional significance of mu-3 receptors in the conventional outflow pathway of the eye and ciliary muscle; (3) identifying a link between mu-3 receptors and NO dynamics in trabecular meshwork and ciliary muscle cells; (4) examining the effect of mu-3 receptor activation on signal transduction events related to NO actions in the eye (cGMP, Ca2+). Information obtained from this project could prove to be useful in the development of agents for the therapy of glaucoma.